Enteric Nervous System Abnormalities in Ulcerative Colitis

In the recent years, there is increasing evidence highlighting the crucial role played by ENS in intestinal inflammation, as demonstrated by the growing numbers of studies looking at both morphological and functional alterations in the ENS and its cellular elements, neurons and glial cells. These observations are the results of investigations carried out in both experimental animal models and in intestinal tissues of patients with inflammatory bowel disease. Although morpho-functional abnormalities of the ENS of UC patients have been consistently reported, additional studies are necessary to better understand the changes in the enteric cells, including neurons (of both submucosal and myenteric layers) and glial cells, which control gut functions, such as colonic motility and secretion, in the inflamed gut. This approach will help to prevent enteric neuropathies associated with inflammation and pave the way to future therapeutic options. Targeting neuronal and/or glial alterations during the course of inflammation may represent a novel approach to diminish the entity of tissue damage as well as the lack of long-term effectiveness of classical immunosuppressant agents used in the treatment of UC. Moreover, additional studies investigating the relationship between ENS and immune cells are warranted in order to carry out an in-depth assessment of the role of neurons, glial cells and their derived factors in the modulation of immune/inflammatory responses in the human gut, in light of establishment of new therapeutic approaches towards the treatment of gut inflammatory diseases. One of the main questions that still need to be addressed to is whether the alterations of the ENS precede or are secondary to the inflammatory process within the gut. This will hopefully help to predict the disease outcome in UC, that until now remains a challenge, and for better understanding of the pathogenesis of this disease. In conclusion, the complex interactions of the ENS and the other systems during gut inflammation require a broad perspective from neurophysiology, biochemistry and immunology to completely understand the regulation of inflammatory processes involved in UC. Therefore, important progress in this field can only be achieved by interdisciplinary approaches. Further research in this direction needs to be done for the discovery of longlasting, effective treatment for inflammatory diseases of the gut

S100B inhibitor pentamidine attenuates reactive gliosis and reduces neuronal loss in a mouse model of Alzheimer's disease

Among the different signaling molecules released during reactive gliosis occurring in Alzheimer’s disease (AD), the astrocytederived S100B protein plays a key role in neuroinflammation, one of the hallmarks of the disease. The use of pharmacological tools targeting S100B may be crucial to embank its effects and some of the pathological features of AD. The antiprotozoal drug pentamidine is a good candidate since it directly blocks S100B activity by inhibiting its interaction with the tumor suppressor p53. We used a mouse model of amyloid beta- (A-) induced AD, which is characterized by reactive gliosis and neuroinflammation in the brain, and we evaluated the effect of pentamidine on the main S100B-mediated events. Pentamidine caused the reduction of glial fibrillary acidic protein, S100B, and RAGE protein expression, which are signs of reactive gliosis, and induced p53 expression in astrocytes. Pentamidine also reduced the expression of proinflammatory mediators and markers, thus reducing neuroinflammation in AD brain. In parallel, we observed a significant neuroprotection exerted by pentamidine on CA1 pyramidal neurons. We demonstrated that pentamidine inhibits A-induced gliosis and neuroinflammation in an animal model of AD, thus playing a role in slowing down the course of the disease

Complementary and alternative treatment in functional dyspepsia

The popularity of complementary and alternative medicine (CAM) in treating functional gastrointestinal disorders (FGIDs) has steadily increased in Western countries. We aimed at analyzing available data on CAM effectiveness in functional dyspepsia (FD) patients

Complementary and alterative treatments in functional dyspepsia

INTRODUCTION AND AIM: The popularity of complementary and alternative medicine (CAM) in treating functional gastrointestinal disorders (FGIDs) has steadily increased in Western countries. We aimed at analyzing available data on CAM effectiveness in functional dyspepsia (FD) patients. METHODS: A bibliographical search was performed in PubMed using the following keywords: "complementary/alternative medicine”, “hypnosis”, “acupuncture” and/or “functional dyspepsia”. RESULTS: In community settings, almost 50% of patients with FGIDs used CAM therapies. Herbal remedies consist in multi-component preparations, whose mechanisms of action have not been systematically clarified. Few studies analyzed the effectiveness of Acupuncture in Western countries, yielding conflicting results and possibly reflecting a population bias of this treatment. Hypnosis has been extensively used in irritable bowel syndrome, but few data support its role in treating FD. CONCLUSIONS: Although some supporting well-designed studies have been recently performed, additional randomized control trials are needed before stating any recommendation on CAM effectiveness in treating FD

Correlation between oesophageal acid exposure and dyspeptic symptoms in patients with nonerosive reflux disease.

Oesophageal acidification induces dyspeptic symptoms in healthy individuals. This study aimed to evaluate the correlation between oesophageal acid exposure and dyspeptic symptoms in patients with nonerosive reflux disease. METHODS: A total of 68 patients with dominant symptoms of heartburn, negative upper gastrointestinal endoscopy and concomitant dyspeptic symptoms participated in the study. The severity of dyspepsia and reflux-related symptoms was evaluated, and 24-h gastro-oesophageal pH-monitoring study was performed in all patients at baseline and after 4 weeks of therapy with esomeprazole 40 mg. RESULTS: Oesophageal basal acid exposure was pathological in 43 patients and normal in 25 patients, with a similar prevalence and severity of individual dyspeptic symptoms in the two groups. A significant correlation between reflux and dyspepsia scores was observed in the subgroup of patients with normal, but not in those with abnormal pHmetry (r=0.4, P=0.04 and r=0.2 P=0.07, respectively). After esomeprazole, a reduction in severity of dyspepsia (>or=50% with respect to baseline) was observed, independent of improvement of reflux-associated symptoms. Improvement in dyspepsia was, however, similar in patients with normal and abnormal basal acid exposure (14/25 vs. 33/43, respectively, P=NS). CONCLUSION: Dyspeptic symptoms coexist in a subset of nonerosive reflux disease patients, but prevalence and severity of the symptoms seems to be independent of oesophageal acid exposure

Endocannabinoid-related compounds in gastrointestinal diseases

The endocannabinoid system (ECS) is an endogenous signalling pathway involved in the control of several gastrointestinal (GI) functions at both peripheral and central levels. In recent years, it has become apparent that the ECS is pivotal in the regulation of GI motility, secretion and sensitivity, but endocannabinoids (ECs) are also involved in the regulation of intestinal inflammation and mucosal barrier permeability, suggesting their role in the pathophysiology of both functional and organic GI disorders. Genetic studies in patients with irritable bowel syndrome (IBS) or inflammatory bowel disease have indeed shown significant associations with polymorphisms or mutation in genes encoding for cannabinoid receptor or enzyme responsible for their catabolism, respectively. Furthermore, ongoing clinical trials are testing EC agonists/antagonists in the achievement of symptomatic relief from a number of GI symptoms. Despite this evidence, there is a lack of supportive RCTs and relevant data in human beings, and hence, the possible therapeutic application of these compounds is raising ethical, political and economic concerns. More recently, the identification of several EC-like compounds able to modulate ECS function without the typical central side effects of cannabinomimetics has paved the way for emerging peripherally acting drugs. This review summarizes the possible mechanisms linking the ECS to GI disorders and describes the most recent advances in the manipulation of the ECS in the treatment of GI diseases

CORRELATES TO ABDOMINAL PAIN IN CONSTIPATION PREVALENT IBS PATIENTS

Background and aim: Symptoms of irritable bowel syndrome (IBS) have been associated to altered motility and sensation. In constipated prevalent-IBS patients, a clear association between bowel habit and abdominal pain remains to be established, and it is not known whether factors related to patients daily life may play a role in symptoms generation. Our aim was to evaluate the association between abdominal pain, bowel habit, demographic factors, alimentary/voluptuary habits and colonic transit in constipated-IBS patients. Material and methods: 68 patients complaining of chronic constipation were selected on the basis of the Rome 3 criteria for IBS. Colonic transit time (CTT) was studied and alimentary attitudes and smoking habit were recorded. Presence of mild or severe abdominal pain was scored, as well as the prevalent pain characteristics, defined as diffuse or localized, chronic or acute, with cramps or gradually distending. Data were analysed by univariate and stepwise multiple logistic regression analysis was also used to verify the risk association between pain and all other variables. Results: 40 patients were classified as constipated and 28 had alternating evacuation. Constipated patients had a lower scholar degree, consumed more laxatives, had a longer transit time in the right colon and scored more chronic pain than alternating ones, but it was not confirmed by multivariate analysis. When severity of abdominal pain was used as discriminating factor, a significant number of subjects reporting severe pain were males (16/30 vs 4/38, p<0.01) and smokers (20/30 vs 4/38, p<0.001). Multivariate analysis confirmed that only smoking was an independent factor associated with severe abdominal pain (OR 14.3, CI 2–99, p= 0.007). Conclusions: Abdominal pain is similarly reported by constipated or alternating IBS patients and it is not associated with colonic transit time or demographics. Smoking is the only factor constantly and independently associated to severe abdominal pain. As smoking does not seem likely to affect colonic transit time we suggest that smoking may act on the visceral perception in IBS-constipated patients

Role of Non-Caloric Carbonated Beverage Preload During a Standardized Solid and Liquid Meal on Colecistokinin and Ghrelin Levels in Healthy Subjects

Background and Aim: The effects of beverages with carbon dioxide on the gastrointestinal system mainly involve the upper digestive tract, with a possible modification of gastric physiology and change in food intake. No data are available on the relationship between non caloric carbonated beverages intake and gastrointestinal hormones levels. We aimed to verify the effect of a sugar-free carbonated beverage (CB) preload compared to a CB without CO2 (DCB) and water (W), during a standardized solid (SM) and liquid (LM) meal, on colecistokinin (CCK) and ghrelin (Gh) release. Subjects & Methods: After 300 ml of CB, DCB and W, a standardized SM or LM was administered at constant rate (100 kcal/5 min) to ten healthy subjects (4 females, aged 22-30 years; BMI 21-24) on six days in a random order (D1: CB+SM; D2: DCB+SM; D3: W+SM; D4: CB+LM; D5: DCB+LM; D6: W+LM). Eating perceptions (desire to eat, hunger, prospective of food consumption) and maximum satiety (MS) as total kcals intake were measured. CCK and Gh were evaluated on blood samples collected at 0, 10 (after beverage), 30, 60 and 120 min. Hormones values are expressed as ratio with body area surface (BSA) and as peak and nadir for CCK and Gh respectively. All data are expressed as mean±SD. Results: Desire to eat, hunger and prospective of food consumption were not different among beverages and meals. Total kcal intakes at MS were significant increased during SM respect to LM for CB (774±209, 585±299, p<0.01), DCB (837±208, 585±280, p<0.01) andW(783±244, 630±353, p<0.01) respectively, without differences among beverages. No differences were found for CCK and Gh among all beverages during SM or LM. Instead, CCK after CB was higher during SM than LM (1.004±0.514, 0.513±0.243, p<0.05) but not after DCB and W (0.790±0.604, 0.849±0.595, n.s.; 0.712±0.473, 0.873±0.431, n.s.) respectively. Moreover, after all beverages, Gh was higher during SM than LM (CB: 0.314±0.100, 0.206±0.099, p<0.05; DCB: 0.288±0.060, 0.145±0.051, p<0.01; W: 0.307±0.083, 0.170±0.085, p<0.01). Conclusions: Liquid meal determined an earlier satiety respect to a solid meal with a parallel decrease of Ghrelin independently of the kind of beverage preload. A CCK decrease was found only during liquid meal after carbonated beverage preload without influence on kcal intake compared with DCB and W. Studies on the influence of carbon dioxide on CCK release nutrients related need to explain this data

Mental Stress Increases Meal-Induced Symptoms Severity by Sympathetic Hyperactivity and Enhanced Endocrine Response in Patients With Postprandial Distress Syndrome

Background and Aim: Previous data show that psychological stress may alter gastric sensorymotor function. Neuro-hormonal mechanisms underlying this phenomenon in dyspeptic patients remain to be clarified. Aim of the present study is to assess autonomic nervous system activity and hypothalamic-pituitary-adrenal (HPA) axis hormones in response to mental stress before and after meal in dyspeptic patients. Subjects and methods: Fifteen patients with postprandial distress syndrome (PDS) (8 M, 21-40 years) and eight healthy controls (4 M, 19-28 years) underwent electrogastrography (EGG) and gastric emptying study (13C-octanoic acid breath test) using a 480 Kcal solid meal. Heart rate variability assessment (LF/HF ratio) by ECG and CRF, ACTH and cortisol on serum samples collected every 30 minutes for 5 hours were also evaluated. Dyspeptic symptoms (postprandial fullness and early satiety) were scored at same time points by analogue visual scale and expressed as sum of total symptoms scores (TSS). The study protocol, with and without a standardized mental stress (MS) test (serial numeric calculations for ten minutes) before the meal, was repeated in a random order in two different days. Results: Dyspeptic symptoms were present only in patients and were exclusively meal-related. In patients, but not in controls, MS significantly increased symptoms severity (TSS: 738±635 vs 288±301, p<0.05). LF/HF ratio was significantly higher in patients during postprandial period with than without MS (5.38±3.48 vs 2.78±0.92; p<0.05), whereas in controls it remained unmodified. In addition, a significant increase of ACTH postprandial levels after MS in patients (stress 6.63±3.11 pg/ml vs no-stress 3.72±2.07; p<0.05) was found, while in controls no modifications were observed. CRF and cortisol were unmodified both in patients and controls. Gastric emptying rate was delayed in 60 % of patients, but it was not influenced by MS. EGG did not show any modification. Conclusions: In PDS patients, concurrent administration of mental stress and meal increases symptoms severity by inducing enhanced sympathetic activity and increased HPA endocrine output. As the gastric emptying looks not altered, we can assume that these neuro-hormonal responses mainly affect gastric sensitive functio

ACHALASIA TREATMENT IMPROVES SPECIFIC SYMPTOMS AND QUALITY OF LIFE: VALIDATION OF AN ACHALASIA SPECIFIC QUALITY OF LIFE QUESTIONNAIRE

Background and aim: Therapies for achalasia aim to patients’ symptom relief, but they affect patient’s quality of life (QoL), too. An ad hoc question- naire evaluating both achalasia-related symptoms and disease related QoL is lacking. Aim: To validate a disease specific QoL questionnaire in perspectively evaluated Italian achalasia patients. Material and methods: 22 consecutive achalasia patients (4 men, age range 19–86 years) were included in the study. At baseline a structured question- naire was used to evaluate both esophageal symptoms and disease specific QoL. Questionnaire graded achalasia-related symptoms severity (dysphagia for solids and liquids, food regurgitation, chest pain, nocturnal cough) from 0 to 3, based on their impact on daily activities. Also a disease specific QoL was evaluated by a self administred questionnaire, the AE-18, that investigated four domains (physical, psychological and social functioning, and sleep dis- turbance). Scores for each item range from 1 (“always”) to 5 (“never”); higher scores corresponding to better quality of life. All patients were questioned before, 1 and 6 months after a specific t reatment regimen, that according to patients clinical status consisted in pneumatic dilation, botulinum toxin injection or surgical myotomy. Results: Patients within each specific treatment groups were the following (3/22 surgical myotomy, 14/22 pneumatic dilation and 5/22 Botox injections, respectively. In the table are reported the baseline demographics and achalasia- related symptoms’ severity and QoL (data are expressed as mean ± SD) within each treatments group. Table 1 Surgery group Dilation group Botox group p Age at diagnosis 42.3 ± 6.5 42.3 ± 13 81.8 ± 4.8 < 0.001 Age at onset of symptoms 39.3 ± 7.5 40.3 ± 12.4 80.8 ± 5.6 < 0.001 Dysphagia for solids 2.7 ± 0.6 2.2 ± 0.7 2.2 ± 0.5 0.5 Dysphagia for liquids 2.0 ± 1.0 2.1 ± 0.7 2.2 ± 0.5 0.9 Regurgitation of undigested food 1.0 ± 1.7 0.7 ± 0.8 0.6 ± 1.3 0.8 Chest pain 0.7 ± 1.1 1.1 ± 1.1 1.0 ± 1.4 0.8 Nocturnal cough 1.3 ± 1.5 1.3 ± 1.2 1.0 ± 1.4 0.9 AE-18 total score 54 ± 14 53 ± 12 53 ± 11 0.9 At both 1 and 6 months of the follow-up, the severity mean scores of dysphagia achalasia-related symptoms severity were significantly reduced compared to baseline (p < 0.05). Similarly, the AE-18 total score was significantly improved (p < 0.001). Conclusions: We showed that therapy-induced improvement of achalasia- related symptoms correlate with a significant improvement of patients quality of life as assessed by a specific questionnaire